The hemoglobin concentration in the sickle erythrocyte is a major determinant of cytoplasmic viscosity and greatly influences the rate and which hemoglobin S polymerizes following deoxygenation. This observation has created much interest in cell volume regulation in the sickle erythrocyte. The identification of factors which cause cell dehydration improves our understanding of the pathogenesis of sickling. The ability to dilute the hemoglobin content of the sickle erythrocyte, which inhibits gelation of hemoglobin S, offers a new therapeutic approach to the treatment of sickle cell disease. The proposed work will focus on several relationships between membrane transport, cell volume regulation, and sickling. It is agreed that during reversible sickling, large "downhill" fluxes of Na, K, and calcium occur. The possibility that these fluxes of ions are involved in cellular dehydration or are the signal for dehydration will be extensively investigated in terms of recent information about passive ion transport in mammalian red cells. A method of deoxygenation has been devised in which ion and water movements which occur with deoxygenation can be studied under controlled conditions. The information gained may lead to an improved understanding of the pathgenesis of sickling. This in turn may produce practical methods, using principles of cell volume regulation, which will inhibit hemoglobin S gelation.